The alloreactive T cell repertoire has been analyzed for responses to two categories of alloantigens: mutant Kb determinants and non MHC-encoded Mis(c) antigens. It was demonstrated by limiting dilution techniques and slope analysis that proliferating F1 responding T cell populations contain distinct subsets capable of recognizing Mls(c) encoded determinants in the context of parental MHC determinants. These finding demonstrate that non-MHC Mls(c) determinants are recognized by responding T cells in association with MHC encoded determinants. Responses to K(b) mutant determinants were evaluated employing radiation bone marrow chimeras, neonatal tolerization, and cold target inhibition in assays of cell mediated lympholysis (CML). The results of such studies demonstrated that the generation of the T cell repertoire to these mutant MHC determinants was not the result of T cell genotype alone or of maturation environment alone, but rather represented the outcome of unique interactions between these two variables.